Granules for pharmaceutical preparations, methods and apparatus for their production

ABSTRACT

Disclosed are improved granular pharmaceutical preparations, together with improved methods and apparatus for preparation of granules for use in such preparations. Such methods are especially useful for making granules for solid oral dose pharmaceutical preparations, and are particularly suited to the production of granules comprising 5-aminosalicylic acid (5-ASA) for the treatment of inflammatory bowel disease. The granules exhibit a more sharply peaked length distribution, and hence aspect ratio distribution, and have a consequently much sharper dissolution profile after further processing.

FIELD OF THE INVENTION

The present invention relates to improved granular pharmaceuticalpreparations, together with improved methods and use of an apparatus forpreparation of granules. Such methods are especially useful for makingsolid oral dose pharmaceutical preparations, for instance thosecomprising granules having an active pharmaceutical ingredient of whichthe release rate needs to be predetermined (controlled) and areparticularly suited to the production of granules comprising5-aminosalicylic acid (5-ASA) for the treatment of inflammatory boweldisease.

BACKGROUND OF THE INVENTION

Many drugs are commonly employed in a granular form for preparingmedical formulations, e.g. solid oral dosage forms. Beside the drug, thegranules may comprise excipients such as surfactants, diluents, ordisintegrating agents. Granules containing active pharmaceuticalingredients (API) can be coated subsequent to the granulation. Bycareful choice of the coating it is possible to control how fast and inwhat part of the digestive system the drug is released. In addition tothe coating, controlling the physical characteristics of granules, suchas size, roughness, morphology and porosity, is important as theseparameters at least partly determine the amount of coating to be used.

Several approaches exist to produce granules of desired properties.These approaches generally involve an initial step of manufacturinggranules followed by a unit operation aimed at sorting the producedgranules according to size, in order to obtain only those granuleswithin a required size range. Granulates can be produced by eitherbuilding up particles from an initial seed or by breaking down a largermaterial into smaller sized particles. Often, cylinder-shaped granulesare subjected to a spheronisation process, which produces sphericallyshaped particles, i.e. particles which for instance roll randomly asthere is not or no longer just a single axis around which the particlecan roll. A non-spheronised cylinder-shaped granule is characterised bythe presence of a single axis around which the granule can roll. In theart, spheronised granules may also be referred to as pelletised granulesor pellets. Dedicated apparatuses exist for spheronising or pelletisinggranules.

Typical operations employed in sorting the granules (spheronised or not)are fluidised beds or various types of sieves. However, the currentlyutilised procedures suffer from a number of weaknesses as will bediscussed below.

WO2001/03089 describes devices for sorting pharmaceutical particlesbased on fluidisation principles. The housing chambers employed in thesedevices are equipped with rotating filters intended to retain particleslarger than a desired minimum while the rotation of the filter portionswill prevent clogging of the filter with (undesired) fine particlesunavoidably formed during the preparation process. Application offluidised beds for separation of particles is mainly useful forseparating particles with aspect ratios close to 1, as the particleswill tend to align with the fluidising stream in a way to minimisefriction, i.e. longer particles can generally not be effectivelyseparated from shorter particles with comparable widths.

US2004/0033266 discloses methods to obtain pharmaceutical particles ofso-called monomodal size distributions. This is achieved byultrasonicating large agglomerated particles resting on a screen with amesh aperture size defining the intended particle size. Theultrasonication will break down the agglomerates into smaller particleswhich will then pass through the apertures and be collected on anotherscreen with smaller holes. The methods are optimally suited for crystalagglomerates, which are held together by electrostatic interactions. Themethods are much less suited for more complex types of particles orgranulates, or those with aspect ratios significantly different from 1.

US2005/0269433 discloses integrated processes for producing granulesfrom dry powders. Granulates produced in an early step of the processare milled and sorted in an intermediate, semi-dry state which isadvantageous when the intermediate is size separated using screens orsieves. However, size separation through sieves has a problem similar tothat of fluidised beds: particles can pass through the holes if theirsmallest dimensions are below those of the holes, and all but very longparticles will eventually pass through the sieve. Accordingly, sievingmethods fail to discriminate moderate to high-aspect-ratio particlesfrom low-aspect-ratio particles.

Some previous methods for production of drug-containing granules, suchas those described in application WO2003/032952, rely on the extrusionof a wet mass containing the drug and a suitable binder through a screenwith a desired size of holes followed by drying and milling to produce agranulate. Separation according to size is then typically performedusing sieves. The sieves are arranged to mechanically vibrate to enhancethe probability that long granules will pass the sieve whilst movingthrough the sieve in their length direction. The sieved granulates inthis class of process are as a consequence thereof generally observed topossess a relatively wide granule length distribution. Such a phenomenonis due to the above-noted characteristics of sieving methods. Thesedistributions are nevertheless generally regarded as an acceptablelimitation by those skilled in the art. As the sieve cannot discriminateon the basis of the lengths of the granules, it follows that thedistributions are effectively width distributions. This has for a longperiod of time not been recognized in this field.

SUMMARY OF THE INVENTION

According to a first aspect of the present invention there is provided apharmaceutical preparation comprising granules of which each has anactive pharmaceutical ingredient and of which each has a predeterminedaxis and the same predetermined cross-sectional profile, wherein atleast 80% by number of those granules, preferably 85%, most preferably90% have an aspect ratio less than 2.2, preferably less than 2.1, mostpreferably less than 2. Each of these percentages is understood toembrace percentages within plus/minus 10%. At least 80% is thereforealso considered to include 70%. It is possible that each of thosegranules has the same active pharmaceutical ingredient.

It is further also possible that those granules form at least 10% bynumber, 30% by number, 50% by number, 70% by number, 90% by number, oreven 100% by number of the pharmaceutically active granules of a singledose of the pharmaceutical preparation.

The granules referred to above are considered to be non-spheronised.

Spheronised granules are considered to have sphere-like shapes and noangular or edge-like features. Often, a spheronised granule rollsrandomly as there is not or no longer just a single axis around whichthe granules can roll. Non-spheronised granules possess angular oredge-like features to the extent that rolling around more than one axisis not possible.

Preferred embodiments of the first aspect of the invention are providedwherein at least 80% by number of those granules, preferably 90%, mostpreferably 95% have an aspect ratio greater than 0.7, preferably greaterthan 0.9, most preferably greater than 1.0. Presently preferredembodiments of the first aspect of the invention are provided whereinthose granules have a median aspect ratio above 1.0, preferably above1.1, most preferably above 1.2, and below 1.7, preferably below 1.6,most preferably below 1.5. Preferred embodiments of the first aspect ofthe invention are provided wherein those granules have a span of theaspect ratio less than 0.9, preferably less than 0.8, more preferablyless than 0.7, even more preferably less than 0.6, most preferably lessthan 0.5.

It is preferable that at least one of the numerical descriptionsprovided above applies to all the granules of the preparation, or whereapplicable, at least to those having an aspect ratio greater than 1.

In each case, such embodiments are able to exhibit a more controlled andreproducible dissolution profile, that is, a greater majority ofgranules dissolve within a given time window after immersion in solvent,and a smaller proportion of granules dissolve outside this window. Suchembodiments can release the majority of their active ingredient after awell-defined interval and are thus especially suited to applicationswhere a well defined release after immersion in a solvent is required,such as in oral dose pharmaceuticals.

Further, pharmacologists prefer to have a well-defined and preferablynarrow aspect ratio distribution, so that further processing,transporting, etc. can more easily be modeled and present lessfluctuations which would otherwise be caused by some of the extremelylarge (or small) granules in the tails of the distribution.

Preferred embodiments of the first aspect of the invention are providedwherein the smallest cross-sectional dimension is between 0.25 mm and2.5 mm, preferably between 0.5 mm and 2 mm, most preferably between 0.6mm and 1.8 mm. In a very suitable embodiment, the smallestcross-sectional dimension is fixed at 0.95 mm

Such embodiments are particularly suitable for the production ofconvenient dose forms including oral dose forms such as tablets, sachetsand filled capsules.

Possible dosage forms which are envisaged by the present applicationare—in addition to the above-mentioned granules—tablets, capsules,sachets or pills. The granules can be used as such as a preferred dosageform, can be filled into capsules or sachets or can be furthercompressed into tablets or pills.

Further dosage forms which are also encompassed by the presentapplication are drinks or syrups, elixirs, tinctures, suspensions,solutions, hydrogels, films, lozenges, chewing gums, orallydisintegrating tablets, mouth-washes, toothpaste, lip balms, medicatedshampoos, nanosphere suspensions and microsphere tablets, as well asaerosols, inhalers, nebulisers, smoking or freebase powder forms anddosage forms for topical application like creams, gels, liniments orbalms, lotions, ointments, ear drops, eye drops and skin patches.

Further encompassed are suppositories which can be used e.g. rectally orvaginally. All these dosage forms are well-known to a person skilled inthe art.

Preferred dosage forms according to the present invention are granules,coated granules, tablets, pellets, suppositories and emulsions. Evenmore preferred are granules and tablets.

Most preferred embodiments of the present invention are represented bygranules, either per se or filled in e.g. a sachet or a capsule orgranules further processed to a tablet or pill. The granules of thepresent invention can all be further processed (e.g. dissolved), as lateas shortly before administration, into any one of the above-mentioneddosage forms.

In the following, the present specification will focus on thedescription of “granules”. However, whenever reference is made to“granules” this term shall encompass all further possible dosage formsas known to a person skilled in the art and in particular those asmentioned above as well.

Preferred embodiments of the first aspect of the invention are providedwherein the granules comprise one or more active pharmaceuticalingredients and, optionally, one or more pharmaceutically acceptableexcipients, such as fillers, binders, etc.

The granules of the present invention can comprise any possible activeingredient which shall be formulated into a pharmaceutical composition.As the present invention is concerned in particular with the provisionof improved properties of the resultant granules—independent of theactual pharmaceutical ingredient used—the invention does not depend onthe selection of the actual active ingredient.

Just as an example, possible active ingredients in that context could beselected from anti-inflammatory compounds, anti-cancer compounds,anti-diabetes compounds, cardiovascular compounds like compounds for thetreatment of high blood pressure, antibiotics, compounds for thetreatment of infertility and compounds for the treatment ofneurodegenerative disorders.

In a particularly preferred embodiment, the active ingredient would bean ingredient which should be delivered with a controlled, e.g. adelayed release. That is, the granules of the present inventioncomprising such an active ingredient might be provided with a coating,or at least a number of those granules might be provided with a coating.Thus, in a preferred embodiment the present invention is directed togranules with coatings and in particular to granules comprising activeingredients which shall be released in a controlled manner, wherebythese granules have a coating.

More preferred, this coating is a pharmacologically acceptable coatingand it is particularly preferred that the coating is an enteric coating,a prolonged release coating or a delayed release coating; all suchcoatings are well known to a person skilled in the art.

As examples, but by no means restricting the present invention, activeingredients which could be provided in such granules for controlledrelease, which comprise a coating, could be selected fromnateglinide)(Starlix®), metoprolol (Seloken ZOK®) and esomeprazole(Nexium®).

Even more preferred, the present invention encompasses ingredients whichare anti-inflammatory pharmaceutical ingredients. Particularly preferredare aminosalicylic acid or pharmacologically acceptable salts or estersthereof, thus being encompassed by the scope of the present claims. Evenfurther preferred embodiments of the invention are provided, wherein theaminosalicylic acid is 5′-aminosalicylic acid (5-ASA). Thispharmaceutical product is often referred to as PENTASA, of which atablet (500) would, for instance, contain 500 mg 5-ASA. Non-medicalingredients are micro crystalline cellulose, ethylcellulose, magnesiumstearate, povidone, and talc.

In that context, whenever reference is made in the following to a“pharmaceutical ingredient” or an “active ingredient”, it shall be notedthat both terms can be used interchangeably; both always encompass thepossibility of using a pharmacologically acceptable salt or esterthereof.

Such embodiments are advantageous in improving the integrity of the doseform in manufacture, storage and use.

Preferred embodiments of the first aspect of the invention are providedwherein the pharmaceutical preparation is suitable for treatinginflammatory bowel disease. Further preferred embodiments of the firstaspect of the invention are provided wherein the pharmaceuticalpreparation is suitable for treating ulcerative colitis, Crohn'sdisease, dyspepsia, high blood pressure, diabetes type I or II,neurodegenerative disorders, inflammatory disorders, cardiovasculardisorders, or cancer. As mentioned above, any active ingredient can beformulated by the present invention; thus, the active ingredient doesnot limit the scope thereof, which is defined only by the scope of theclaims.

Such embodiments are of particular utility and exhibit improvedproperties when compared with other commonly-available treatments forsuch conditions.

Preferred embodiments of the first aspect of the invention are providedwherein the granules are compressed into a tablet. Other preferredembodiments of the first aspect of the invention are provided whereinthe granules are enclosed inside a sachet. Yet other preferredembodiments of the first aspect of the invention are provided whereinthe granules are enclosed inside a capsule.

According to a second aspect of the present invention there is provideda method of producing a pharmaceutical preparation comprising the stepsof: producing granules having a predetermined cross-sectional profileand a predetermined axis; sorting the granules into at least onefraction according to their aspect ratio; and selecting for furtherprocessing those granules in a given fraction or given fractions. Thestep of sorting the granules is effected by passing the granules througha length separator.

Such embodiments are able to produce granules which are non-spheronisedand which exhibit a more controlled and reproducible dissolutionprofile, and are thus especially suited to applications where a welldefined release after immersion in a solvent is required, such as inoral dose pharmaceuticals.

The granules may form at least 10% by number, 30% by number, 50% bynumber, 70% by number, 90% by number, or even 100% by number of thepharmaceutically active granules of a single dose of the pharmaceuticalpreparation.

In preferred embodiments of the second aspect of the invention, thelength separator comprises a surface having cavities formed therein, thesurface being arranged to follow a predetermined path such that agranule on the surface having a predetermined relationship between thedimensions of a given cavity and the length of the granule will fall andbe classified into a given fraction.

Such embodiments are especially effective at rapidly and effectivelyachieving the required granule distributions on laboratory andproduction scales. Such embodiments are able also to achieve acontinuous, rather than discontinuous, process, and can produceimprovements in yield and process time.

Preferred embodiments of the second aspect of the invention are providedwherein the granules are prepared by: passing a homogenised wet massthrough an extruding screen having apertures with predetermineddimensions formed therein; and comminuting the extruded mass to formgranules.

Such embodiments are convenient to form on production scales and allowwell-defined aspect ratios to be determined.

Preferred embodiments of the second aspect of the invention are providedwherein the surface is a cylinder, the predetermined path is rotaryabout the axis of the cylinder, and a receptacle for collecting thegranules to be classified into a given fraction is positioned off-axisof the cylinder.

Such embodiments are able to be applied to large quantities of granuleswithout requiring a large equipment footprint.

In preferred embodiments of the second aspect of the invention thecylinder is arranged to rotate at less than 1 revolution per second.Preferred embodiments of the present invention are provided having aninner diameter of between 10 cm and 200 cm. Particularly preferredembodiments are provided wherein the cylinder is arranged to rotate atperipheral surface speeds of less than 1 m/s.

Such embodiments are able to produce a particularly improved granuleaspect ratio distribution, and may also improve the time in which for acertain number of granules a preferred aspect ratio distribution isreached.

In preferred embodiments of the second aspect of the invention, thecavities of the surface are each suitable for hosting a single granuleof predetermined dimensions.

Such embodiments are able to particularly effectively extractwell-defined fractions of granules.

Preferred embodiments of the second aspect of the invention are providedwherein granules not selected for further processing are further againcomminuted and subsequently further again sorted according to theiraspect ratio. Particularly preferred embodiments of the second aspect ofthe invention are provided wherein the granules not selected for furtherprocessing are further again sorted in the same process as the sortingof the granules in an earlier step of sorting.

Such embodiments allow a reduction in waste and improvement in usableyield, and in particularly preferred embodiments permit such animprovement in yield without significant increase in apparatusfootprint.

According to a third aspect of the present invention, there is provideda use of a length separator in a method for producing a pharmaceuticalpreparation, wherein the use occurs during selecting granules of whicheach has a predetermined axis and the same predetermined cross-sectionalprofile and of which at least a number have an active pharmaceuticalingredient. Preferably, each of the granules has an activepharmaceutical ingredient, and even more preferably, that activepharmaceutical ingredient is the same for each of the granules. Thegranules are non-spheronised granules. In a preferred embodiment, themethod for producing a pharmaceutical preparation comprises applying acoating to selected granules so that the active pharmaceuticalingredient is released with a predetermined rate. Preferably, the lengthseparator comprises a surface having a number of identically preshapedcavities formed therein. Each cavity is suitable for hosting a singlegranule. The surface is arranged to follow a predetermined path, so thata granule initially kept in a cavity will fall out of the cavity at aposition along the predetermined path. That position depends on thelength of the respective granule. The use of this particular lengthseparator allows for an efficient and straightforward way of separatinggranules having a length shorter than a predetermined length. It ispossible to set the predetermined length such that the selected granulesare no longer likely to fracture up into smaller granules. Accordingly,the amount of total surface area of the granules is stable in that itwill not significantly alter during further processing. On that basis itis possible to apply a coating to a large batch of the selectedgranules, such that a coating has a predetermined thickness and therelease rate of the active pharmaceutical ingredient can accurately becontrolled.

The selected granules may form at least 10% by number, 30% by number,50% by number, 70% by number, 90% by number, or even 100% by number ofthe pharmaceutically active granules of a single dose of thepharmaceutical preparation.

BRIEF DESCRIPTION OF THE DRAWINGS

To better explain the claimed invention, and to show how the same may becarried into effect, reference will now be made, by way of example only,to the accompanying Drawings, the contents of which are described in thefollowing paragraphs.

FIG. 1 shows schematic representations of an example of a lengthseparator showing:

-   -   a) the working principle (in cross-section);    -   b) an enlarged section of the separator shown in a); and    -   c) an example showing a collector, here in the form of a trough        comprising an upper stationary part receiving the selected        granules and a slightly sloped lower vibrating part conveying        the selected granules towards an outlet.

FIG. 2 discloses granule length distributions by count of two batches ofuncoated 5-ASA granules according to the measurement protocol givenbelow (left axis: relative distribution; right axis: cumulativedistribution).

FIG. 3 illustrates granule length distributions of 5-ASA granulesseparated in a cavitied cylinder separator with cylinders with cavitiesof:

-   -   a) 1500 μm diameter (PTD-X05-255=cylinder fraction;        PTD-X05-254=trough fraction);    -   b) 1750 μm diameter (PTD-X05-257=cylinder fraction;        PTD-X05-256=trough fraction); and    -   c) 2000 μm diameter (PTD-X05-259=cylinder fraction;        PTD-X05-258=trough fraction), respectively (left axis: relative        distribution; right axis: cumulative distribution).

FIG. 4 shows photographs of granules sorted using a cavitied cylinderseparator where (a) is the trough fraction and (b) the rotating cylinderfraction.

FIG. 5 shows granule length distributions for:

-   -   a) current production; and    -   b) granules obtained by the cavitied cylinder separator using a        cylinder with a cavity size of 2000 μm and tear-drop shaped        cavities    -   (left axis: relative distribution; right axis: cumulative        distribution). In FIG. 5 a, full lines represent granule length        distributions before the coater; dashed lines represent granule        length distributions after coating. In FIG. 5 b, dashed lines        represent granule length distributions before the coater; full        lines represent granule length distributions after coating. The        dotted vertical line indicates the exemplary desired maximum        size of the granules, 2000 μm).

FIG. 6 a is a probability plot comparing the distribution of thedissolution data at 90 minutes of a comparative sample of coatedgranules (“PENTASA tablet granules”) and a sample of classified andcoated granules prepared in accordance with the present invention(“PENTASA 95% sachet”).

FIG. 6 b shows a representation of the statistical significance, bymeans of the “F-test”, of the distribution data displayed in FIG. 6 a.

FIG. 7 shows the aspect ratio distribution of a sample of fractionatedand unfractionated granules of PENTASA compositions, together withcomparative data for the granules of Example 5.

DETAILED DESCRIPTION OF THE INVENTION

Without wishing to be bound by any particular theory or explanation ofthe advantages of the present invention, in the making of the presentinvention it was observed that granules comprising an activepharmaceutical ingredient tend to fragment during the coating process,particularly when the granules have a relatively large aspect ratio. Onecan easily imagine that a long, rod-shaped granule, having a high aspectratio, will tend to fragment across the length direction during furtherprocessing. Such behaviour is a feature of geometry, and particularly ofaspect ratio, provided that the major dimensions of the granule are muchlarger than the microstructure of the granule. On the other hand, shortgranules (of aspect ratio less than 1) will tend to abrade on edges andfaces during processing to a slightly more spherical configuration.However, such abrasion, also referred to as attrition, is not consideredto be a form of spheronisation, as the granules will not reach a stagein which more directions for rolling become available, or in which adominant predetermined axis and/or cross-section is not recognisable.The granules still have edge-like features.

While some authors define aspect ratio as ratio of longest to shortestdimension, or of shortest to longest dimension, when discussing anextruded granule having a predetermined axis (e.g. the axis ofextrusion) and being of defined cross-section (e.g. the extrusioncross-section), it is most useful to define aspect ratio in terms ofgranule length along its predetermined axis, i.e. the extrusion axis,divided by the smallest cross-sectional dimension (the diameter in thecase of particles having a circular cross-section). In the presentapplication, we use this definition since it is the ratio between thesedimensions that is considered to have the greatest impact on fractureproperties. The present invention, however, has application beyondextruded granules to any similarly-formed granules.

Typically, extruded granules and similarly-formed granules have arecognisable axis, for example an axis of rotational or mirror symmetry,along which the cross-section perpendicular to that axis issubstantially similar, barring broken corners or slight variations inthe manufacturing process, or even slight tapering of the granule towardone or both ends. This is typically the extrusion axis in extrudedgranules. In any similar bulk granules, it can also be defined as theaxis perpendicular to which the dominant cross-sectional profile issubstantially similar to that of the other granules. So, while thegranules may individually vary in length along such an axis, they willall exhibit substantially similar cross-sections perpendicular to it.

The term “similarly-formed granules” encompasses granules which have thecharacteristics of extruded granules in terms of a predetermined axisand an identical predetermined cross-sectional profile, even thoughthese granules are formed by a process that is different from extrusion.A moulding technique could for instance impose a predetermined axis anda predetermined cross-sectional profile onto a long granule, which mayafter its production, fragment into shorter granules in the same way asextruded granules do.

The term “predetermined axis” may be seen to refer to an axis imposed ona granule to be formed even before the granule is formed. The axis ispredetermined in the sense that it is determined by the apparatus usedfor forming a lengthy fiber-like material prior to its fragmentationinto granules. A predetermined axis may thus be defined as an axisimposed onto the granule to be formed before its formation in agranulation process. A mold also imposes an axis onto a granule beforethe actual formation of the granule.

A similar view may apply to the term “predetermined cross-sectionalprofile”. It is imposed onto the granule before its formation in agranulation process, by the apparatus used for forming a lengthyfiber-like material, which results upon fragmentation of that materialinto the granules.

It is clear that granules subjected to a spheronisation process are notor no longer granules having a predetermined cross-sectional profile.

It is particularly useful in considering the general teaching of thisapplication to regard granules having a predetermined axis and the samepredetermined cross-sectional profile to be granules having apredetermined axis and, perpendicular to that axis, the samepredetermined cross-sectional profile at at least three axiallyseparated positions along that axis. Adopting such a definition canachieve the advantages of the invention whilst ensuring that granuleswith minor deformities and irregularities fall within the scope of thepresent invention and granules which are substantially spherical orirregular are excluded from the definition.

If the aspect ratio as defined above is large, the granules have rod,prism or cylindrical type geometry, and applied forces are believed totend to snap the granule at some point along this axis, reducing itslength but not substantially affecting its cross-section. On the otherhand, if the aspect ratio as defined above is small, applied forces arebelieved to tend to abrade or crush the granule, altering itscross-section. If the aspect ratio as defined above is close to or lessthan one, the probability of applied forces fracturing the granule alongthis axis is believed to become low or minimal, and abrasion andcrushing may become the dominant fracture mode.

Accordingly, a definition of aspect ratio as given above is consideredto be both very useful for characterising the present invention andunderstanding its behaviour, and is also entirely consistent with aspectratios less than 1, which are, in other less useful definitions ofaspect ratio, not defined. When the length is longer than the largest ofthe cross-sectional dimensions, however, this definition of aspect ratiobecomes identical to the alternative definition as largest dimensiondivided by smallest dimension.

On the one hand, fragmentation of granules during coating increases theoverall surface to be coated. Hence, if a certain amount of coatingliquid, calculated for achieving a specific coating thickness, is used,the resultant coating thickness is reduced. On the other hand, if thefragmentation of granules occurs towards the end of the coating process,the newly generated granule surfaces tend to receive only a small amountof coating or no coating, so that the overall dissolution properties ofthe granules will deviate from that for which the amount of coatingliquid was calculated. Moreover, the dissolution profile is likely tobecome faster and less well-defined, in that some of the granules willdissolve well in advance of others, as those granules having received alower amount of coating on a freshly generated surface will dissolvemore rapidly. Such granules, in oral dosage forms, may release theiractive ingredient undesirably early, e.g. in the stomach rather than theintestine. As a result, it was concluded that it is preferable toexclude granules exceeding a certain length from the coating process inorder to accomplish a more uniform coating of the granules.

Therefore, there is a need in the art for granules having well-definedlength distributions, and particularly granules whose lengthdistribution strongly disfavours granules having an aspect ratio suchthat they fragment during further processing, including coating. Thereis also a corresponding need for methods and apparatus to separategranules for pharmaceutical compositions according to their length sothat a well-defined length distribution of granules, and therefore awell-defined dissolution and release profile for active ingredients, maybe obtained.

Embodiments of the present invention are of use in the pharmaceuticalfield for producing granules comprising a desired active pharmaceuticalingredient or even a combination of several active ingredients.

The granules used as starting material for the present inventionsuitably have a common cross-sectional profile. The three-dimensionalshape may be cylindrical, ellipsoidal, or any other shape desired, forexample a triangular, rectangular or other polygonal prism. In thepresently preferred embodiments of the invention the shape iscylindrical, i.e. the diameter of each granule is along its lengthessentially identical to the diameter of any of the other granules.Thus, only the length dimension varies. However, the present inventionis also applicable to mixtures having a variety of profile geometries inthe granules, for example a mixture of circular and hexagonal prismaticgranules.

The granules are suitably produced by extrusion. The extruder comprisesa screen, which has numerous holes with a diameter of between 0.6 and1.8 mm, preferably 0.9 mm. The thickness of the screen is between 0.9and 2.0 mm; preferably, the thickness of the screen is 1.5 mm. The holesare arranged with a geometry which imparts the desired cross-sectionalprofile to the extruded granules, for example circular holes forproducing cylindrical granules, or triangular holes for triangularprismatic granules. Each hole can have the same cross-section throughthe screen or be tapered in either direction, compared to any of theother holes. Preferably, the holes are tapered, each hole having across-section at the inlet side of the screen that is larger than thecross-section at the outlet side of the screen, the preferred outletdiameter is 0.9 mm and the preferred inlet diameter is 0.95 mm.

After the extrusion, the granules may be dried in a suitable device.Advantageously, the drying device is a fluid bed. However, otherpossibilities known by the skilled person may also be used, such as ovendrying, irradiation with e.g. infrared, ultraviolet or microwaves, andfreeze-drying.

If a fluid bed is used, it may be designed in such a way that thedwelling time in the fluid bed is approximately 2 hours. However,shorter or longer times are also contemplated, depending on thedimensions and composition of the granules.

In some cases the fluid bed is separated in two parts. In the first partthe granules are dried on the surface to avoid their sticking together.In this part a random mixing of the granules takes place. In the secondpart of the fluid bed the final drying takes place and the granules areguided through the fluid bed by a suitable pattern of holes in thebottom plate of the fluid bed.

When the granules are dry they are discharged from the fluid bed and maybe transferred to a mill to reduce the length of the granules. Themilling process is preferably conducted with a conical mill, howeverother milling types may be used, such as bead mills, jet mills,blenders, or manual comminution. The milling may generate a small amountof fines that may be removed by sieving before the granules are readyfor treatment in accordance with the present invention. However, thepresent invention is also realisable without milling.

The wet mass employed in the production of the granules used in thepresent invention may be prepared by any suitable process dependingamong other factors on the specific active pharmaceutical ingredient andthe pharmaceutical formulation. The exact composition of the wet masswill determine the parameters of the extrusion and optional drying step;selection of suitable parameters is well within the capacity of thoseskilled in the art.

It is also conceivable that the wet mass, as extruded into fiber-likematerial, is chopped into shorter fragments of such fibers, to influenceor even fix the length of the majority of the granules produced in thisway. This may result in a more uniform length distribution, with awell-defined narrow peak. The selection of granules having a requiredlength distribution may then be applied as a form of quality control.

To arrive at granules being an embodiment of the claimed invention, amethod of selecting granules having the required length distribution isthus in any case preferably employed.

One embodiment of such a method uses a length separator to sort thegranules, which comprises a surface provided with a number of pre-shapedcavities, each suitable for hosting one of the granules. Such a surfacemay be termed a cavitied surface. The surface is arranged to follow apredetermined path so that from each cavity a granule hosted thereinwill fall out at a drop-out position along the path. Each drop-outposition is determined by the longest dimension of the granule hosted inthe respective cavity.

The length separator further comprises a collector for collectinggranules from at least one predetermined drop-out position. Anembodiment of such a length separator comprises a rotatable cylinderhaving an essentially horizontally oriented axis provided on theinterior surface with a number of cavities, for instance an array ofcavities.

The term “essentially horizontally” also comprises embodiments in whichthe rotating cylinder is slightly inclined, e.g. the cylinder may beinclined 1-15 degrees, suitably 2 to 6 degrees, relative to thehorizontal position. The inclination is typically in the direction of anoutlet, such that the particles treated in the length separator areassisted by gravity in the movement from the inlet towards the outlet.In other arrangements, the reverse arrangement is possible, with theoutlet and higher than the inlet end, to maximise dwell time in theseparator.

Although this embodiment of a length separator is very practical, otherembodiments are possible. It is for instance possible that the surfaceprovided with the pre-shaped cavities is part of a conveyor belt and/orthat the cavities are provided at an exterior surface of a cylinder. Theprinciples of operation of other equivalent arrangements, and how theyare to be configured in an effective manner, will be clear to theskilled person from the present description.

FIG. 1 a discloses a schematic drawing of an exemplary length separator13. The length separator 13 comprises a cylinder or mantle 1 internallyprovided with cavities 2, preferably in the entire circumferencethereof. The arrow depicts the direction of the rotation. Inside thecylinder 1, a trough 3 is provided, as at least part of a collector.When the cylinder is rotated granules below a certain cut-off value willbe discharged in the trough. FIG. 1 b shows a detail of the apparatusshown in FIG. 1 a. The granule 4 is of a length below a certain cut-offvalue and is therefore received by the trough 3, while the length ofgranule 5 is above the cut-off value and therefore remains in thecavitied cylinder.

The cavities in the interior surface of the cylinder are provided in anarray. The cavities may be provided in a pattern or randomly and thecavities are usually substantially evenly distributed. Suitably,cavities are provided in essentially the entire circumference of thecylinder. For an efficient separation, cavities are provided alongessentially the entire length of the cylinder, such as at least 60%,preferably at least 70% and most preferably at least 85% of the length.

The shape of the cavities may be any geometrical form, such ascylindrical, teardrop shaped, hemispherical, box shaped, polyhedral,etc. In a certain embodiment, the cavities are cylindrical, such thatthe centre axes of the cavity cylinders are directed towards therotational axis of the rotating cylinder. In preferred embodiments,asymmetrical or “tear-drop” cavities may be provided. In such a“tear-drop” part of the cavity, the leading part of the cavity withrespect to the direction of movement of the cavity, is relativelyshallow. The trailing part of the cavity is relatively deep, the deeperpart of the cavity being in the trailing part of the cavity.

In some configurations, different cylindrical portions of the cylinder,being relatively displaced axially lengthwise, may have differentlyconstructed and/or dimensioned cavities in order to extract variouslength fractions; combinations of different cavities at any particularaxial portion are also contemplated, depending on the selectioncriteria. The cavities may be prepared by various methods providing thedesired geometrical shape. Thus, the cavities may be prepared byembossing, milling, drilling etc. of a surface. The cavities may beindents, in which case the surface may be referred to as an indentedsurface.

The surface which is provided with the number of pre-shaped cavities ispreferably a stainless steel. This has the advantage that the surfacecan be cleaned up and prepared to a standard required for use of thesurface within the pharmaceutical industry. Furthermore, the cavitiescan be formed by local deformation of the surface; forming the cavitiesby embossing (or deep drawing) in a stainless steel cylinder ispossible. Such cavities exhibit a particular benefit when granules of anactive pharmaceutical ingredients are treated with a length separatorhaving such a surface, that as the cavities have a smooth surfacewithout edges (as opposed to cavities formed by, e.g., drilling), thegranules rarely get stuck in the cavities and are therefore less proneto breakage.

The geometrical shape of the cavities depends on the desired separationprofile, and thus the distribution of granule lengths to be obtained. Inone configuration, wherein the surface provided with a number ofpre-shaped cavities is part of a cylinder, the cavities have parallel tothe surface a longest dimension ranging from 0.5 to 3 mm. In the event acavity is cylindrical, this longest dimension corresponds to thediameter. In a preferred configuration, the diameter is between 1 to 3mm, more preferred 1.5 to 2.5 mm. The diameter is an important parameterin determination of the so-called cut-off value, i.e. the value at whichlarger particles are excluded. In one configuration, the cavity istapered along a direction into which the surface will follow thepredetermined path. The latter configuration is particularly suitablefor preventing granules from being blocked in the cavity. Othervariables which may be adjusted to optimise the effectiveness of thecavities include depth or cavity and steepness of the cavity bendingedges.

The length separator is advantageously operated at conditions wherecentrifugal forces exerted on the particulate matter are not significantcompared to the gravitational force. A centrifugal acceleration may becalculated from ω²r, where ω denotes the rate of rotation (in s⁻²) and rthe radius of the predetermined path, or in an advantageous embodimentof the length separator (in m). The acceleration may be compareddirectly to the gravitational acceleration, g, which is of the value9.81 m/s². Thus, for a length separator of 400 mm diameter rotating atapproximately 30 rpm the centrifugal acceleration exerted on granules inthe cylinder will be around 0.05 m/s², considerably smaller than theacceleration due to gravity.

In configurations in which the surface of the length separator providedwith cavities is cylindrical, the diameter of the cylinder is typicallybetween 10 cm to 100 cm. The diameter may be larger in certainembodiments, for example those in which granules of lower density areprocessed. Generally, however, the diameter is selected in the range ofto 90 cm, suitably 40 to 70 cm, to obtain a desired productivity interms of amount of granules (kg) treated per hour. The length of thecylinder may be selected in accordance with the desired capacity. Ingeneral, the length is between 10 cm and 200 cm, suitably 100 to 200 cmand preferably 130 to 160 cm. A typical relationship between length anddiameter is from 0.5:1 to 5:1; in presently preferred configurations,from 1:1 to 3:1. In a particularly presently preferred configuration thediameter is about 60 cm and the length of the separator is about 150 cm.

For a configuration where a rotatable cylindrical surface is providedwith cavities, the rate of rotation is generally selected so as toobtain a sufficient productivity. Generally, the rate of rotation isselected together with the diameter to obtain a centrifugal accelerationbelow ½ g, preferably below 1/10 g, more preferred below 1/100 g. In acertain configuration, the diameter of the essentially horizontallyrotating cylinder is 10 cm to 200 cm and the rotational speed may beselected in the range of 10 to 100 rpm (revolutions per minute),preferably 20 to 50 rpm, and most preferably 25 to 40 rpm.

The granules discharged from the cavities when the essentiallyhorizontally-oriented cylinder is rotated may be recovered by anysuitable means. In one embodiment, the length separator comprises, as acollector, a trough located in the cylinder, said trough being capableof receiving granules discharged at a predetermined drop-out position,i.e. at a certain elevation of the cavities in which the granules havebeen accommodated. Generally, the trough extends over the entire lengthof the length separator. Positioning the trough off-axis of the cylindermay be particularly suitable for collecting a particular lengthdistribution; the position and dimensions of the trough may be adjustedeasily by those skilled in the art to tune the distribution obtained.

Following collection, the selected granules may then be conveyed to anoutlet for further treatment. In one embodiment of the invention, thegranules are transported in a chute after they have been recovered inthe trough. The chute is connected to the outlet. The chute may beslightly sloped and/or vibrating to assist the selected granules in themovement towards the outlet. The chute may be a part of the trough ormay be provided separately. In some embodiments, the trough comprises anupper stationary part receiving the selected granules and a slightlysloped lower vibrating part conveying the selected granules towards anoutlet. The separation of the upper stationary and the lower vibratingpart provides for easy servicing of the apparatus. Other means fortransportation of the selected granules may include a screw conveyor.

FIG. 1 c shows a view of a particular length separator such as may beusable in one embodiment of the method of the present invention. Thelength separator comprises a rotatable cylinder 1, at the interiorsurface provided with cavities.

The cylinder 1 is rotated at a constant speed by an electric motor (notshown). In the cylinder a trough is positioned. The trough consists ofan upper stationary trough 6 for receiving the selected granules and aslightly sloped lower vibrating conveyor 7. The selected granules(termed the in-size fraction) are conveyed in the lower vibratingconveyor 7 of the trough towards an exit 8. The granules discharged fromthe exit 8 are received by a transporter 9. The particles received bytransporter 9 are transported to a storage container (not shown). Theremaining granules in the rotating cylinder (termed the oversizefraction) are discharged to a transporter 10 and conveyed to a storagecontainer.

The upper stationary trough 6 of the trough is mounted on a rotatableaxle 11, using bearings. The lower vibrating conveyor 7 of the trough isvibrated in axial direction by the rotation of a disc provided withbuttons. The lower trough 6 of the trough is flexibly mounted on theaxle 11 through a plate spring 12 for holding the vibrating conveyor.

The oversize fraction may be recycled for a further treatment in thelength separator. The recycling step may include that the longerparticles are comminuted by milling and returned for renewed treatmentin accordance with step b). The granules for recycling may be milled bya conical mill or similar means.

The granules being embodiments of the present invention and beingobtainable by embodiments of the method of the invention generally havea narrower granule length distribution than those obtainable by meresieving of equivalent starting granular material. Granule sizedistributions, and the descriptive statistics thereof, are determined inaccordance with the “Determination of Granule Length Distribution” asset out in below “Example 2”. Such a method is applicable to both coatedand uncoated particles.

During any of the processing steps from granulation to selectinggranules, small fines may be produced by a process of friction relatedattrition. This, however, does not alter the overall shape of thegranules and is certainly not a form of spheronisation.

The selected granules may be used for the preparation of apharmaceutical composition. According to preferred embodiments of thepresent invention the selection step is followed by a step of applyingonto the selected granules a pharmaceutically acceptable coatingmaterial.

Further to the active pharmaceutical ingredient, the granules maycontain one or more pharmaceutically acceptable binders or fillers or amixture thereof. Suitable binders include acacia, gelatin, hydroxypropylcellulose, hydroxypropylmethyl cellulose, methyl cellulose, polyethyleneglycol (PEG), povidone, sucrose, starch or a mixture of any of these.Povidone (polyvinyl pyrrolidone, PVP) is a preferred binder. Binders maybe used in a total amount of 1 to 10, or 2 to 8, or 3 to 7, or 4 to 6,or 5% by weight of the granules. Suitable fillers include inter aliamicrocrystalline cellulose. Fillers may be used in a total amount of 10to 70, or 20 to 60, or 40 to 50, or 50% by weight of the granules.

Both binders and fillers as well as possible further excipients are wellknown to a person skilled in the art and can be selected in a routinemanner.

The granules may be coated in any coating device applicable to theprocess. The skilled person will readily know which devices would besuitable for the present process, such as for example a fluid bedsystem, e.g. a Kugel coater. In some embodiments, the coating materialis applied to the selected granules as a solution, and coating of theselected granules is provided upon evaporation of the solvent. Thegranules are preferably coated with a polymer dissolved in a suitablesolvent for the polymer, preferably an organic solvent such as acetone.As the granules selected for coating are unlikely to further fragmentinto shorter granules, it is possible to use a coater in which theforces exerted on the granules are relatively high, so that the coatingcan occur within a relatively short space of time.

In order to be able to determine the amount of polymer that has to beapplied to the granules, the surface area is measured, or known on thebasis of earlier measurements carried out for granules produced andselected in the same way.

Any type of measurement is in principle suitable. However, usually themeasurement will be based on image analysis of a representative andstatistically relevant sample of the selected granules. The imageanalysis will further be referred to below. Based on a known correlationbetween the amount of polymer per surface area and the dissolution rateprofile, the amount of polymer needed can be predicted from thedetermined surface area of the granules.

The selected coating polymer inter alia depends on the desired releasepattern, e.g., delayed release or extended release. Release-modifyingcoating agents which extend the release of the active-pharmaceuticalingredient include ethyl cellulose, carnauba wax, shellac or a mixturethereof. Enteric or delayed release coating agents includepolymethacrylate, commercially available in the form of Eudragits, e.g.Eudragit L 100 or Eudragit NE 40 D. When an extended release pattern isdesired, ethyl cellulose is the most preferred coating agent.

From an article published in 1988 in “Drug Development and IndustrialPharmacy”, 14(15-17), 2285-2297, by G. Ragnarsson and M. O. Johansson,it is known that smaller granules (i.e. granules with a large surfacearea per volume) would for a given thickness of the coating, provide alarger release rate than larger granules (i.e. granules with a smallersurface area per volume) would demonstrate for the same thickness ofcoating. In other words, if the smaller granules should have the samerelease rate as the larger granules, then the coating applied to thesmaller granules should be thicker so that the release rate can be thesame for each of these particles. This highlights the importance of avery uniform granule size distribution, in particular a narrow aspectratio distribution where granules are cylinder-like and have the samecross-sectional profile and dimension. On the basis of this article andinsights presented in the International Journal of Pharmaceutics, 63(1990) 189-199, an article by M. Eriksson, C. Nyström and G. Alderborn,both incorporated herein by reference, a person skilled in the art willbe able to establish how much coating is needed for a given surface areato obtain a certain release rate. Hence, if the number of those granulesare known and the aspect ratio distribution is known, then the correctamount of thickness can easily be calculated. If needed, routineexperiments can verify the correctness of the parameters applied. Inless optimal situations, it is also a task which lies within thestandard skills of a developer in this field to find suitable correctivemeasures for establishing the optimal amount of coating.

The granule size distribution of the coated granules of the presentembodiment of the invention is similar to that of the uncoated granulesobtainable by the method of the present invention, as the coatingthickness does not have a substantive influence on the length of thegranules, and the granules have been selected to avoid the occurrence ofsignificant fragmentation in the coating process.

The granule size distribution, or the granules aspect ratiodistribution, can be obtained on the basis of microscopy combined withimage analysis, for instance as described by Cynthia S. Randall inChapter 6, Particle Size Distribution, of the book titled “PhysicalCharacterisation of Pharmaceutical Solids” edited by Harry G. Brittain,1995.

In a preferred embodiment, suitable for the treatment of inflammatorybowel disease, the active pharmaceutical ingredient is 5-aminosalicylicacid (5-ASA) or any salt or ester thereof. The salts of 5-ASA may beacid addition salts, in particular the hydrochloride, but anypharmaceutically acceptable, non-toxic organic or inorganic acid may beused. 5-aminosalicylic acid is also known by synonyms includingmesalazine, 5-aminosalicylic acid, 2-hydroxy-5-aminobenzoic acid;3-carboxy-4-hydroxyaniline, 5-asa, mesalamine, rowasa and5-amino-2-hydroxybenzoic acid, and has the molecular formula C₇H₇NO₃ anda molecular weight of 153.14. It is registered under Cas registry number89-57-6 and Einecs 201-919-1.

Also salts formed with the carboxylic acid group may also be used. Asexamples alkali metal salts (K, Na), or alkaline earth metal salts (Ca,Mg) may be mentioned; however, any pharmaceutically acceptable,non-toxic salt may be used. The Na and Ca salts are preferred.

Applicable esters include e.g. straight chain or branched C₁-C₁₈ alkylesters, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl,hexyl, heptyl, octyl, nonyl, decyl, lauryl, myristyl, cetyl, andstearyl, etc., straight chain or branched C₂-C₁₈ alkenyl esters, e.g.vinyl, allyl, undecenyl, oleyl, linolenyl, etc., C₃-C₈ cycloalkylesters, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl, etc., aryl esters, e.g. phenyl, toluoyl,xylyl, naphthyl, etc., alicyclic esters, e.g. menthyl, etc., or aralkylesters, e.g. benzyl, phenethyl, etc.

Generally, the selection of the active ingredient depends on theselected type of, formulation, the disease pattern, especially the siteand type of the disease, and the desired release of the activeingredient.

The physical state and solubility characteristics of the 5-ASAderivatives must be taken into account when selecting a suitable carriercomposition for the ingredient. The preferred active pharmaceuticalingredient at present is the free acid, 5-aminosalicylic acid.

The effective oral dose depends on the extent of the disease and foradults usually amounts to 0.5-1.0 g four times a day, or alternatively2.0-4.0 g once daily. Generally about 20 mg/kg body weight of 5-ASA or asalt or ester thereof (calculated as 5-ASA) will be the recommendedinitial daily dosage subject to adjustment in accordance with theobserved results of the treatment.

At present, the preferred release pattern is a continuous releasefollowing arrival in the small intestine. This release was originallydesigned so as to enable the pharmaceutical composition, e.g. Pentasa®,to be effective against both Crohn's disease and ulcerative colitis.

However, in case it should be desirable to secure an early release inthe small intestine (in the case of Crohn's disease) or a delayedrelease until arrival in the colon (in the case of ulcerative colitis),the release pattern can be controlled by varying different parameters ofthe coating. The skilled person will be able to readily determine howsuch release conditions may be achieved; nonetheless, for the sake ofcompleteness the skilled person may find the disclosure of WO 81/02671,which is hereby incorporated by reference, of some benefit in achievinga particular release profile.

In a certain presently preferred method, the granules comprise 5-ASA.Thus, the granules may be prepared by wet mixing of 5-ASA with asolution of a binder, such as polyvinylpyrrolidone (PVP, Povidone) inwater (e.g. 21.3% w/w). Specifically, 5-ASA and an aqueous solution ofPVP are mixed and added to the extruder. Alternatively, 5-ASA and theaqueous solution of PVP may be mixed in the extruder. In either case,the wet mass consisting of 5-ASA and PVP is extruded through a screenand allowed to fall into the device for drying of the wet granules.

The aqueous solvent is preferably water of a suitable quality, but maycontain additives, such as chelating agents, antioxidants, reducingagents, buffers and pH adjusting agents.

The granules comprising 5-ASA as the active pharmaceutical ingredientmay specifically be prepared as described in, e.g., WO 97/23199, WO03/032952 or WO 2004/093884, incorporated herein by reference. In oneparticular embodiment, the granules contain prior to coating 5-ASA andbinder only, as described in WO 2004/093884.

In certain aspects the present method is utilised for the preparation ofprolonged release tablets, sachets or capsules useful for the treatmentof ulcerative colitis or Crohn's disease. In one embodiment, the coatingmaterial is a cellulose derivative, such as ethyl cellulose. In sometablet embodiments, the excipients comprise a tablet carrier, such asmicrocrystalline cellulose, a lubricant, such as magnesium stearate andoptionally further excipients such as talc.

In the below disclosure, including Examples, we will demonstrate howpharmaceutical preparations being embodiments of the present inventionand comprising the advantageous granules of the present invention haveimproved properties compared with those having granules not fallingwithin the scope of the claims

Comparative Example A Production of Granules for Tablets Comprising5-ASA (Water Based Granulation Process)

The manufacturing process for 5-ASA tablets can be divided into a numberof steps: preparation of granulation liquid; mixing of 5-ASA with waterand PVP; extrusion; fluid bed drying; milling; sieving; coating; sievingagain, purging, dry blending with excipients, and compression to tablets

Step 1: For one batch of granulation liquid 118.4 kg of water was filledinto a Müller drum. The mixer was put into position and started. 32 kgof PVP was slowly sprinkled onto the water and the mixer was allowed torun a fixed time until all PVP was dissolved.

Step 2 and 3: 640 kg of 5-ASA was placed in a vibrating Prodima hopperand by the use of a conveyor the 5-ASA was transported up to a weightbelt feeder dosing the 5-ASA into a continuous production line. In thefirst part of the production line the 5-ASA and the water solution ofPVP were mixed to a wet mass before being transported into the extruder.After extrusion of the wet mass of 5-ASA and PVP/water through a screenmesh 0.9 mm, the granules fell directly into the fluid bed dryer.

Step 4: The fluid bed dryer was divided into two main sections. In thefirst section, the granules were dried on the surface to prevent themfrom sticking together. In this section of the fluid bed, a randommixing of the granules took place. After a certain residence time, thegranules were moved into the second part of the dryer where the actualdrying took place. In the second part of the dryer the granules wereguided by the use of the drying air through the dryer.

When the granules were dry they were allowed to fall into a drum placedunder the fluid bed. The fluid bed was constructed in such a way thatthe overall dwelling time in the fluid bed was approximately 2M hours.

Step 5: The drums containing the dry granules were placed upside down ontop of the mill and the granules were gently milled using a screen.After passing the mill, the granules were allowed to fall into a drum.

Step 6: The granules were sieved using a Mogensen vibration sieve withscreen dimension 0.8 mm. Granules which passed the screen werediscarded.

Step 7: 200 kg of sieved granules were coated in a Kugel coater, being afluid bed system, with a coating liquid consisting of ethylcellulosedissolved in acetone.

In order to be able to determine the right amount of polymer necessaryto apply on the granules to get the desirable dissolution rate profile,the surface area of the granules was measured prior to the coatingprocess. The prediction of the quantity of polymer that was necessary toapply on the granules has been developed based on the fact that there isa correlation between the amount of polymer per surface area and thedissolution rate of the granules. Once the surface area characteristicsfor a given granulation size distribution is known, the calculatedquantity of polymer may be repeatedly used on comparable batches ofgranules. After finishing the coating process, the coated granules wereloaded into a drum for further processing.

Step 8: After the coating process, the coated granules were sieved in aProdima rotation sieve. Large lumps were discarded.

Step 9: After sieving, the batch of coated granules was divided into twodrums for purging with compressed air or nitrogen. The granules werepurged for 6-14 hours, although shorter times, such as 30 minutes, arealso considered reasonable in practice. This purging process wasnecessary to reduce the amount of residual solvent (acetone) in thecoated granules.

Step 10: 178.56 kg coated Pentasa granules were weighed out and loadedinto the Prodima blender together with 69.34 kg microcrystallinecellulose. After mixing for 210 seconds the blender was stopped. 0.335kg magnesium stearate and 3.02 kg talc were added to the blend and theingredients were mixed for 90 seconds. The blend gave approximately335,000 tablets.

After mixing the blend was discharged into Muller drums ready forcompression.

Step 11: The final blend of coated granules and excipients wascompressed on a rotary tabletting machine. Weight of each of thetablets: 750 mg. Dedusting of the tablets was performed as an in-lineprocess with the tabletting machine. After dedusting the tablets wereloaded into bulk containers holding approximately 30,000 tablets each.

Comparative Example B Preparation of 5-ASA Granules for Sachets

A batch for the production of 180,000 sachets of prolonged releasegranules was provided as outlined below, using the quantities indicatedin Table 1.

TABLE 1 Ingredients for 5-ASA granules for sachets. ConstituentsQuantity Specification 5-ASA 180 kg Ferring PVP 9 kg Ph. Eur. † Water,33.3 kg * Ph. Eur. † purified Ethyl 1.9 kg ** Ph. Eur. † celluloseAcetone 188 kg * Ph. Eur. † * Evaporates during production. ** Theamount of ethylcellulose was adjusted to ensure the desired dissolutionprofile of the finished product. † Ph. Eur. refers to the currentedition of the European Pharmacopeia at the time of filing of thepresent application.

The manufacturing method followed closely the manufacturing methoddescribed in Example A, with some modifications. In particular, notablets were made, so no dry blending with excipients was performed(Step 10) and no tableting performed (Step 11). Also, the amount ofethylcellulose is reduced as there is no compaction to a tablet, andthus a reduction in the amount of coating applied is needed to obtainthe desired dissolution profile.

The manufacturing process for the formulation can be divided into anumber of steps: preparation of granulation liquid; granulation of 5-ASAwith water and PVP; extrusion; fluid bed drying; milling; sieving;coating; sieving; and purging.

Thus, the process for the manufacture of granules for sachets differsfrom the tablet process in step 7 as explained below, and steps 10 and11 of Example A were not included.

Step 7: When the coating step was performed and followed by productionscale sieving acceptable release characteristics were achieved. Afterfinishing the coating process, the coated granules were loaded into adrum for further processing.

This batch provided granules with the composition listed in Table 2.

TABLE 2 Composition of granules for sachets 5-ASA 94.3% by weight  PVP4.7% by weight Ethylcellulose 1.0% by weight

Example 1 Demonstration of Classification of Granules by CavitiedCylinder Separator

Two batches of uncoated granules of 5-ASA were produced according tocomparative Example A (i.e. the product of Step 6), and these granuleswere applied to a laboratory scale cavitied cylinder length separator.

The separator had a rotatable cylinder having a diameter of 400 mm and alength of 500 mm; the inclination of the cylinder was fixed at 4° andthe rotational speed of the rotating cylinder was 32 rpm. The cylinderwas provided with a steel mantle embossed with tear-drop shapedcavities. In other words, the cavities had the shape of half-spheres orhalf teardrops as cross-sectioned along their axes. The cavity isoriented with its axis along the direction of the predetermined pathwhich the surface is arranged to follow; in this case the axis isoriented along the tangential direction of the cylinder.

Initially, granules from one batch were applied to the cavitied cylinderseparator furnished with cavities of 1500 μms, 1750 μms or 2000 μmsdiameter, respectively. The length distribution of the starting materialwas similar to that shown in FIG. 2, and the results of theclassification experiments are shown in FIGS. 3 a to 3 c showing thelength distributions of the trough and the rotating cylinder fractions.Examples of granules obtained in the trough and the rotating cylinderfractions are depicted in FIGS. 4 a and 4 b respectively.

Therefore, it is demonstrated that such a method is capable ofdiscriminating long granules from shorter granules, and that thedistribution of lengths, and thus aspect ratios, obtainable from thismethod is sharply defined.

Example 2 Determination of Granule Length Distribution

The Granule Length Distribution can be determined by any suitablemethod. Although each method may have its own shortcomings, it isusually possible to correct for these, so that a suitably accurateresult can be obtained. In general it will be possible to verify theoutcome by a manual assessment of the length of each granule, using forinstance microscopy. This would then also provide the corrective measureto improve the accuracy of the method employed. A convenient, accurateand more automatic determination is based on image analysis.

The median length and the amount of granules >2000 μm may be determinedby using a method of image analysis, distributing the granules on apresentation plate by vibration. This method was selected for thepresent example. The equipment used was a fully automated image analysisequipment, known by the trade name of VideometerLabXY. The measurementswere performed by backlight using a 1600×1200 pixel black and whitecamera with a pixel size of 0.024 mm. The lens used on the camera was amultispectral lens with a magnification of 1. The presentation plate hada size of 23×29 cm and the granule density was approximately 12granules/cm². The sample measured was approximately 8000 granules.

The image analysis was performed by scanning the presentation in araster manner with an overlap between the individual images of 500 μm.The images were analysed individually, overlapping granules wereexcluded and duplicate granules already detected in a previous imagewere neglected. A Hough circle transformation filter was used to detectand exclude standing granules. The entire presentation plate was coveredby 10×10 images. The software determined the length of a granule by abounding box principle, not using a principal axis measure since thisprovides statistically “noisy” results due to a substantiallyrectangular shape of the granules.

Of course, in certain embodiments in which a particularly large numberof granules have aspect ratio close to or less than 1, a significantlyhigher proportion of granules will be found in measurement to bestanding on end and will thus be excluded by the Hough circle filter.The skilled person will recognise such results, and will understand thatin such cases, the measured aspect ratio distribution, determined by theabove method, will exclude such granules from the count and thedistribution. Nevertheless, even in such cases the benefits of havingthe measured aspect ratio distribution as defined in the claimedinvention will apply, as those particles of aspect ratio close to 1 areconsidered to be statistically far less likely to suffer undesirablefracture events during coating. In such cases, the skilled person willstill recognise such an embodiment as lying within the scope of thepresent invention, even if a significant proportion of granules havebeen excluded from the measurement. In many cases encountered inpractice, however, the proportion of granules so excluded is generallyexpected to be small, and thus not to significantly affect the measureddistribution.

It is also possible that extra effort is made to obtain the length ofeach of the granules, thus also those standing on one end. For instancea method of tracing these in the image and manipulating these for“manual” assessment of the length, using microscopy, is notinconceivable. Obtaining a correction value that can then be applied tothe more automatically formed data is envisageable. A fully manuallycarried out assessment of the length of each granule will of courseallow for a very accurate determination of the length distribution,respectively aspect ratio distribution.

The following data was measured on every granule and presented in anoutput file: bounding box length; bounding box width; area; ferretdiameter, max; ferret diameter, min; theoretical surface area;theoretical volume.

The data generated in summary for the entire sample was: median ofbounding box length; D10 of bounding box length; D90 of bounding boxlength; span of bounding box length; theoretical specific surface area;count percentage>2000 μm; number of particles analysed.

Ferret diameter was calculated based on an angular resolution of 5 andall values are given in mm with a resolution of 0.01 mm.

Span is calculated as (D90−D10)/D50, where D90 and D10 are the 90^(th)and 10^(th) percentiles of the distribution, respectively, and D50 isthe median.

Derivable from any of the bounding box length values and distributionsare corresponding aspect ratio values and distributions, obtainable bydividing the bounding box length by the extruded granule diameter.

The granule length characteristics of the materials obtained using thethree different rotating cylinders as set out in Example 1 and measuredby the method of the present Example are summarised in Table 4. In eachcase, the granules were passed once through the cavitied cylinderseparator.

All given data, values and summary statistics unless otherwise statedrefer to number or count of granules rather than, for example, valuesper unit mass or per unit volume.

TABLE 4 Granule characteristics of selected granules. Cavity Median sizelength % > % < Batch Fraction (μm) (μm) Span 2000 μm 2000 μm 1 Trough1500 1264 0.76 8.5  Cylinder 1500 2079 0.81 45.6 1 Trough 1750 1136 0.380.3  Cylinder 1750 2008 0.89 49.8 1 Trough 2000 1530 0.42 1.18 Cylinder2000 2342 0.63 25

Two different batches were then each passed through the cavitiedcylinder for 5 consecutive cycles, i.e. after each cycle ofclassification the cylinder fraction was passed through the cavitiedcylinder separator again and the trough fractions weighed and eventuallypooled. A cylinder with 2000 μm-diameter tear-drop shaped cavities wasused in this process. The results are summarised in Table 5.

TABLE 5 Granule characteristics of selected granules. Cavity Median sizelength % > % < Batch Fraction (μm) (μm) Span 2000 μm 2000 μm 1 Trough2000 1530 0.42 1.2 Cylinder 2000 2517 0.50 7.6 2 Trough 2000 1484 0.542.7 Cylinder 2000 2426 0.49 6.7

For batch 2, 17.5 kg of starting material was applied to the cavitiedcylinder separator, and the results achieved by weighing each fractionfrom each cycle of the 5-cycle process are summarised in Table 6.

TABLE 6 Removed fractions of 5-ASA granules in 5 consecutive cycles ofseparation in a cavitied cylinder separator equipped with a cylinderwith 2000 μm diameter tear-drop shaped cavities. Run no. Weight (g)Percentage Cumulative percentage 1. 2970 24 24 2. 1200 9.7 33.6 3. 375 336.7 4. 260 2.1 38.8 5. 110 0.9 39.6

The specific surface areas of each of the two fractions of granules weremeasured after 5 cycles through the separator with the cylinder with2000 μm diameter tear-drop shaped cavities and compared to correspondingvalues for the starting materials. The results are presented in Table 7.

TABLE 7 Specific surface areas of 5-ASA granules before and afterclassification by 5 cycles through a cavitied cylinder separatorequipped with a cylinder with 2000 μm tear-drop shaped diametercavities. Specific surface area Batch Fraction (cm²/g) 1 Startingmaterial 63.4 Trough 65.5 Cylinder 61.0 2 Starting material 63.1 Trough63.5 Cylinder 62.4

The classification experiments performed showed that the cavitiedcylinder separator was capable of producing an in-size fraction with amedian granule length of ˜1500 μm and a span of ˜0.5. This is by farsuperior to the sieving technique which produced granules with a medianlength of 1800-2000 μm and a span of ˜0.8. The cavitied cylinderseparator was thus able to produce a fraction of granules with a smallermedian length and a much more narrow size distribution. Furthermore, thespecific surface area obtained by fractionating granules in the cavitiescylinder separator showed a higher specific surface area for the trough(in-size) fraction than for the cylinder fraction.

Example 3 Influence of Parameter Values on Cavitied Cylinder SeparatorClassification Process

To further describe the influence on different operating parameters onthe outcome of the cavitied cylinder separator classification, anotherset of experiments was performed using a batch of uncoated 5-ASAgranules (produced according to comparative Example A). The cavitiedcylinder separator was equipped with a cylinder with 2000 μm-diametertear-drop shaped cavities, and the granulate was classified in 3consecutive cycles conducted as described in Example 1. During theexperiments different values for the feed rate and the rotational speedwere tested. The results obtained by weighing the different fractionsare summarised in Table 8.

TABLE 8 Mean and relative standard deviation of final measurements. Thelast column is the fraction/percentage removed of the 42.3% w/wavailable Settings Mean RSD % of the RPM Feed rate (kg) (%) (%)available 36 56 38.3 0.9 90.5 25 56 38.2 1.9 89.8 36 3 30.3 0.7 71.4 253 40 1.8 94.6

From Table 8 it can be seen that the output was influenced by therotational speed of the cylinder at a low feed rate, while the outputobserved at a high feed rate was unaffected by the rotational speed ofthe cylinder.

The granule length distribution of experiments performed at high feedrates and different rotational speeds were determined to evaluate if theoutput of the cavitied cylinder was consistent regardless of therotational speed of the cylinder. The length distributions of theresulting granules were determined by image analysis as per Example 3and are summarised in Table 9.

TABLE 9 Granule length characteristics of the starting material andtrough fractions Settings Median, Percentage larger RPM Feed rate (kg)length (μm) Span than 2000 μm (by weight) Starting material 1869 0.9857.7 36 56 1468 0.57 3.9 25 56 1409 0.58 2.6

The overall conclusion on the capacity and efficiency is that regardlessof the feed rate and rotational speed the cavitied cylinder was capableof extracting ˜90% of the granules available in the size range desired.The granule length distribution of the trough fraction was in the sizerange desired.

Example 4 The effect of the sorting method on coating

Breakage of the granules during the coating step may be problematic dueto difficulties arising in predicting the dissolution profile of thecoated granules. This is relevant for both manufacturing processesdescribed in comparative Examples A and B. In order to examine how themethod of the present invention affects the subsequent coating procedurein comparison to the method of comparative Example A, a set ofexperiments was set up.

A batch of granules was prepared as described in comparative Example A,and the length distributions before and after coating were measured.Uncoated granules from the batch were classified in a cavitied cylinderseparator and then coated as described in comparative Example A. Thecavitied cylinder separator employed in the experiment contained anarray of tear-drop shaped cavities of 2000 μm size. Length distributionsof uncoated granules classified by treatment with the cavitied cylinderseparator and of the length sorted granules after coating were measured.The results of the length distribution measurements are shown in FIG. 5.

From FIG. 5 a it is seen that the range of the granule lengthdistribution was narrowed from 645-4900 μm to 600-2500 μm by the coatingprocess of the current method. This shows that long granules were brokenduring the coating process. The median length was reduced from 1954 μm(RSD 7.3%) to 1441 μm (RSD 4.5%). The result of this breakage was anunpredictable outcome of the coating process. In contrast, the granulesproduced using the method of the present invention do not suffer fromthis drawback as seen in FIG. 5 b. These results are considered to holdfor any granule having a microstructure much smaller than the granulediameter, and particularly for granules of pharmaceutical preparationshaving a diameter of between 0.25 mm and 2.5 mm.

Example 5 In-Vitro Dissolution of Coated 5-ASA Granules

This example investigates the effect of the cavitied cylinder separatorclassification of 5-ASA granules on the variation of their dissolutionbehavior. Thus, the variation in dissolution of cavitied cylinderseparator classified granules for a sachet (“PENTASA 95% sachetgranules”) is compared with that of unclassified granules for a tablet(“PENTASA tablet granules”). The classified granules, prior to coating,had a median aspect ratio of 1.4 and span of 0.6.

Tablet granules are generally coated with an excess of coating(ethylcellulose) compared to the sachet granules in order to compensatefor the effect of the subsequent compression step. For comparing thedissolution of the coated, dried and sieved tablet granules with thesachet granules, samples of the tablet granules are withdrawn during thespraying phase, after an amount of coating has been applied thatcorresponds to the coating amount applied on the sachet granules. Thedata sets are therefore directly comparable in all relevant factors.

Ten samples of (unclassified) coated PENTASA tablet granules werewithdrawn from routine production batches. Eight samples of classifiedand coated PENTASA 95% sachet granules were withdrawn from test andvalidation batches. Following an in-house test protocol, the in-vitrodegree of dissolution of each of the samples was determined as afunction of time. Data analysis was carried out with the Minitab15.1.1.0 software, developed by Minitab Inc., USA.

The 90 minutes dissolution results and the respective statistics aresummarized in Table 9 below.

TABLE 9 Statistics for the dissolution (90 minutes) of coated PENTASA95% sachet and PENTASA tablet granule batches for samples withdrawnduring the spray phase at a coating factor of 2.0 · 10⁻⁴. Mean Type ndissolution Variance S.D. R.S.D. PENTASA 95% 8 34.1% 19.0 4.4% 12.9%sachet PENTASA 10 40.1% 157.0 12.5% 31.2% tablet granules S.D. =standard deviation; R.S.D. = relative standard deviation

At 12.5%, the standard deviation of the dissolution of comparativePENTASA tablet granules is 2.8 times larger than that of PENTASA 95%sachet granules obtained in accordance with the present invention(4.4%). Moreover, the variance (spread) of the dissolution results forthe inventive product is much more narrow (19.0) than for thecomparative, unclassified product (157.0).

For the PENTASA 95% sachet and PENTASA tablet granule samples, thedistributions of the dissolution results are not significantly differentfrom normal distributions (see FIG. 6 a). Thus, the Anderson-Darlingtest for correspondence of the distributions with a normal distributiongives p=0.32 for PENTASA 95% sachet and p=0.12 for PENTASA tabletgranules.

Since the dissolution results suggest a normal distribution (see FIG. 6a), the variations in dissolution of PENTASA 95% sachet and tabletgranules can be compared using an F-test. The F-test demonstrates thatthe variation in dissolution of coated PENTASA 95% sachet granules issignificantly lower than the variation in dissolution of coated PENTASAtablet granules (p=0.01) (FIG. 6 b).

Having further optimised the process for manufacturing scale, sixbatches of uncoated PENTASA sachet granules (fractionated) and eightbatches of uncoated PENTASA tablet granules (unfractionated, sieved)prepared in a comparable manner to those set out above in the instantExample were analysed for length distribution as set out in Example 2.Aspect ratio distributions were calculated based on the lengthdistributions with length having been divided by the extruded diameterof the granules (0.8 mm). The results are shown graphically in FIG. 7,and the statistics pertaining thereto are summarised in Table 10, thedata of Example 5 being included for comparative purposes also. It isevident from these figures that the distribution of unfractionated(sieved) tablet granules is more sharply peaked with a considerablysmaller tail extending beyond the median value.

TABLE 10 Statistics for the aspect ratio distribution of uncoatedPENTASA sachet and PENTASA tablet granule batches. Aspect PENTASAExample 5 PENTASA ratio sachet granules tablet statistic (fractionated)(fractionated) (unfractionated) D10 1.1 1.1 1.1 Median/D50 1.4 1.4 1.7Span 0.6 0.6 0.9 D90 2 2 2.7

A reduction in such a tail contributes to the advantageous properties ofgranules being embodiments of the present invention. Of course, asmaller improvement is observed with a smaller reduction in the tail.Accordingly, the characteristic values set out above represent thepreferred embodiment.

However, as noted in the Summary of the Invention, and as set out in theappended claims, granule distributions which exhibit any sharply peakeddistribution and reduced tail are also of value, and exhibit someimprovement in the dissolution properties over and above the dissolutionproperties of granules not falling within the scope of the claimedinvention. It will be within the ambit of the skilled person to vary theparameters of the selection method used to arrive at a pharmaceuticalpreparation falling within the claimed scope. The skilled person willalso undoubtedly be able to arrive at the claimed pharmaceuticalpreparations with a variety of selection methods. However, it is thegranules themselves having the required distribution properties whichare considered to impart many of the benefits of the invention,regardless of how they are produced and selected.

Particularly, embodiments wherein at least 80% by number of thegranules, preferably 85%, most preferably 90% have an aspect ratio lessthan 2.2, preferably less than 2.1, most preferably less than 2 areconsidered to exhibit degrees of improvement in the dissolutionproperties of the pharmaceutical preparation through the reduction inthe tail above the median. In some cases, it may be desired to narrowthe distribution further, and embodiments wherein 80%, 85% or even 90%of granules have aspect ratio less than 1.9, 1.7, 1.5 or 1.2 may also bepreferred.

Similarly, embodiments wherein at least 80% by number of the granules,preferably 90%, most preferably 95% have an aspect ratio greater than0.7, preferably greater than 0.9, most preferably greater than 1.0 arealso considered to exhibit improvements in the dissolution properties ofthe pharmaceutical preparation through reduction in the tail below themedian.

The percentages referred to above include percentages within a range ofplus/minus 10%. At least 80% is therefore also considered to include70%. Embodiments wherein the granules have a median aspect ratio below1.7, preferably below 1.6, most preferably below 1.5 are also consideredto exhibit improvements in the dissolution properties of thepharmaceutical preparation through improvements in the centring of thedistribution around a preferred value. In some cases, it may be desiredto bring the median aspect ratio as close to 1 as possible, and soembodiments having a median aspect ratio below 1.4, 1.3, 1.2 or 1.1 willalso be preferred.

And yet, embodiments wherein the granules have a span of the aspectratio less than 0.9, preferably less than 0.8, most preferably less than0.7 are also considered to exhibit improvements in the dissolutionproperties of the pharmaceutical preparation through improvements in thecentral sharpness of the distribution. Similarly, if it is preferred tobring the median aspect ratio particularly close to 1, it may also bevery useful to apply the techniques of the present invention to produceembodiments having span of the aspect ratio lower than 0.5, lower than0.4 or even lower than 0.3.

In cases where the pharmaceutical preparation is provided in sachets,the amount of granules per sachet can be about 2 grams, corresponding toabout 2000 granules. However, also other amounts may be suitable fororal dosage.

All such embodiments can be realised in methods as disclosed above, withsuitable parameter choices which are well within the ambit of theskilled person.

1. A pharmaceutical preparation comprising granules of which each has anactive pharmaceutical ingredient and of which each has a predeterminedaxis and the same predetermined cross-sectional profile, wherein atleast 80% by number of those granules have an aspect ratio less than2.2.
 2. The pharmaceutical preparation of claim 1, wherein at least 80%by number of those granules have an aspect ratio greater than 0.7. 3.The pharmaceutical preparation of claim 1, wherein the granules have amedian aspect ratio above 1.1 and below 1.7.
 4. The pharmaceuticalpreparation of claim 1, wherein those granules have a span of aspectratio less than 0.9.
 5. The pharmaceutical preparation of claim 1,wherein the smallest cross-sectional dimension is between 0.25 mm and2.5 mm.
 6. The pharmaceutical preparation of claim 1, wherein at least anumber of the granules is provided with a coating.
 7. The pharmaceuticalpreparation of claim 6, wherein the coating controls the release of theactive pharmaceutical ingredient.
 8. The pharmaceutical preparation ofclaim 1, wherein the active pharmaceutical ingredient comprises ananti-inflammatory ingredient.
 9. The pharmaceutical preparation of claim1, wherein the active pharmaceutical ingredient is 5-aminosalicylicacid.
 10. A method of producing a pharmaceutical preparation comprisingthe steps of: producing granules having a predetermined cross-sectionalprofile and a predetermined axis; sorting the granules into at least onefraction according to their aspect ratio; and selecting for furtherprocessing those granules in a given fraction or given fractions,wherein the step of sorting the granules is effected by passing thegranules through a length separator.
 11. The method of claim 10, whereinthe granules remain free from characteristics which result from aspheronization process, before the granules are subjected to the step ofsorting.
 12. The method of claim 11, wherein the length separatorcomprises a surface having cavities formed therein, the surface beingarranged to follow a predetermined path such that a granule on thesurface, having a predetermined relationship between the dimensions of agiven cavity and the length of the granule, will fall and be classifiedinto a given fraction.
 13. The method of claim 11, wherein the granulesare prepared by: passing a homogenised wet mass through an extrudingscreen having apertures with predetermined dimensions formed therein;and comminuting the extruded mass to form granules.
 14. The method ofclaim 10, wherein the surface is a cylinder, the predetermined path isrotary about the axis of the cylinder, and a receptacle for collectingthe granules to be classified into a given fraction is positionedoff-axis of the cylinder.
 15. The method of claim 10 wherein thecavities of the surface are each suitable for hosting a single granuleof predetermined dimensions.
 16. The method of claim 10, wherein theselected granules have the properties of the granules of claims 1 to 6.17. The method of claim 10, wherein the selected granules are furthercoated with a pharmaceutical coating suitable for treating inflammatorybowel disease.
 18. The method of claim 10, wherein granules not selectedfor further processing are further again comminuted and subsequentlyfurther again sorted according to their aspect ratio.
 19. The method ofclaim 18, wherein the granules not selected for further processing arefurther again sorted in the same process as the sorting of the granulesin an earlier step of sorting.
 20. A method for producing apharmaceutical preparation, comprising using a length separator duringselection of granules of which each has a predetermined axis and thesame predetermined cross-sectional profile and of which at least anumber have an active pharmaceutical ingredient.
 21. The methodaccording to claim 20, wherein the method for producing a pharmaceuticalpreparation comprises applying a coating to selected granules so thatthe active pharmaceutical ingredient is in use released with apredetermined rate.
 22. The method according to claim 20, wherein thelength separator comprises a surface having a number of identicallypre-shaped cavities formed therein, each cavity being suitable forhosting a single granule, the surface being arranged to follow apredetermined path, so that a granule initially kept in a cavity willfall out of the cavity at a position along the predetermined path,wherein that position depends on the length of the resepective granule.